Disclosed embodiments relate generally to aerosol formulations and medical devices, systems and methods for delivering the same. More particularly, disclosed embodiments relate to compositions, systems and methods for delivering medicaments transnasally into the lungs.
Aerosolized medicines are frequently used to treat individuals suffering from respiratory disease. For example, one known method for treating cystic fibrosis (CF) includes restoring hydration to the affected airway surfaces via the inhalation of a hypertonic osmolyte solution, which draws water onto the airway surface. Known methods often administer a seven percent (7%) hypertonic saline (HS) solution. Rehydration of the lubricant periciliary layer (PCL) of the airway surface facilitates mucus clearance (MC) and, therefore, the removal of inhaled infectious agents.
Known methods for delivering aerosolized medicaments include the inhalation of aerosols orally i.e., via an oral mouth piece or a spacer inserted into the patient's mouth. Some known systems for oral inhalation include nebulizer devices, such as jet nebulizers, vibrating mesh nebulizers or ultrasonic nebulizers, or metered dose inhalers (MDIs), or dry powder inhalers (DPIs) to generate respirable aerosol particles (e.g., particles that are <10 μm in diameter) from a liquid medicament, suspension and/or dry powder. Such known systems and methods for oral delivery, however, often present an undesirable time burden on the patient. For example, some known systems require 10-20 minutes to deliver a single dose of medication. For subjects with chronic pulmonary disease for which the treatment regiment includes multiple daily aerosol treatments, the time burden associated with oral drug delivery via jet nebulizers can become substantial. It is not uncommon for patients undergoing treatment for cystic fibrosis to spend 2-3 hours per day on the recommended treatments (Hume et al., Am J Respir Crit Care Med. 2007 Nov. 15; 176(10):957-69 Sawicki et al., J Cyst Fibros. 2009 March; 8(2):91-6).
Moreover, some studies of treatment protocols for cystic fibrosis have suggested that an increased number of treatments per day and/or delivery of higher amounts of salt. For example, two studies have described (1) the short term (two weeks) beneficial effects of inhaled hypertonic saline (HS) four times daily on pulmonary function, MCC, and quality of life (Donaldson et al., N Engl J Med. 2006 Jan. 19; 354(3):241-50) and (2) the long term (one year) benefits of inhaled HS twice daily on luring function and reduction in pulmonary exacerbations (Elkins et al., N Engl J Med, 354(3):229-40 (2006)). A comparison of the Donaldson versus Elkins suggests that the “more salt” delivered, the greater the benefit in lung function. In particular, subjects in the Donaldson study exhibited a mean improvement in lung function (147 ml improvement in FEV1) with four times daily administration (3.6 ml of 7% HS predicted pulmonary deposition), which as approximately twice the improvement that was achieved in the Elkins study (68 ml improvement in FEV1) with B.I.D. dosing (1.58 ml of 7% HS predicted pulmonary deposition). Thus, as treatment regimens are improved to maximize the benefits of HS administration, the time burden associated with oral drug delivery via jet nebulizers will likely be exacerbated.
In addition to the undesirable time burden associated with known methods for oral delivery of aerosolized medicaments, known methods of periodic delivery over relatively short time periods (e.g., 5 to 20 minutes per treatment) results in the delivery of medicaments as concentrated “boluses”, which can be undesirable. The delivery of medicaments as a bolus leads to a rapid increase of the active therapeutic agent at the targeted location over a short period of time, often at levels above the necessary therapeutic concentration. Similarly, bolus delivery can lead to high systemic exposure to such agents. Such peak local and systemic concentrations following bolus administration of inhaled aerosols can lead to undesirable safety and tolerability profiles, which may prevent adoption of the therapy into the standard of care. For example, chronic inhaled corticosteroids have been shown to have disease-modifying impact on the rate of lung function decline in CF (Ren et al, J Pediatr., 153(6):746-51 (2004 de Boeck et al., Eur Respir J, 37(5): 1091-5 (2011)). Such methods, however, are accompanied by patients' decreased linear growth, and increased insulin/oral hypoglycemic use due to the systemic exposure. As such, inhaled corticosteroids are not recommended for general treatment of CF lung disease (Flume et al, Am J Respir Crit Care Med. 2007 Nov. 15; 176(10):957-69).
In response to the high time burden associated with oral delivery and/or the desire increase the mass of salt delivered, some known nebulizers have been developed to deliver an aerosol dose more quickly, such as, for example, within two to five minutes. Although such known systems and methods may slightly shorten the treatment duration, even short aerosol administrations of several different therapeutic agents several times per day can result in a significant treatment burden. Moreover, as discussed above, some therapeutic agents may not be suitable (effective and/or safe) for administration via an aerosol bolus delivered over short periods.
For example, delivery of up to 12% HS was evaluated (Robinson et al., Thorax. 1997 October; 52(10):900-3), and resulted in the conclusion that HS concentrations higher than seven percent are not well tolerated using known methods of aerosol delivery. Lack of tolerability of HS therapy can be related to high rates of emission of NaCl mass from the nebulizer mouthpiece, which leads to high exposure of oropharyngeal surfaces to HS. Similarly, the high rates of NaCl mass deposition in the lung can lead to adverse events such as chest tightness, cough and acute decreases in lung function (Elkins et al). In chronic obstructive pulmonary disease (COPD), high rates of NaCl delivery initiate histamine release, which contributes to airway spasm (Taube et al. Am J Respir Crit Care Med. 2001 Nov. 15; 164 (10 Pt 1: 1810-5). On a cellular level, administration of high rate of NaCl mass to the airway epithelium substantially dehydrates the airway epithelial cells, which can lead to cell shrinkage, inhibition of ciliary beat frequency and release of inflammatory stimuli leading to pulmonary inflammation (Zhou et al., Journal of Cystic Fibrosis Vol, IOSupplement 1, Page S I 8). Accordingly, using known methods to increase the rate of delivery of an aerosolized medicament can be undesirable.
Other known methods for delivering aerosolized medicaments include transnasal delivery of the aerosolized medicament to the affected airways. Some known systems for transnasal delivery include a long, relatively narrow nasal cannula, through which the aerosolized medicament is transported. Such known systems and methods for transnasal delivery, however, often result in undesirable rainout and/or sputtering of the medicament as it passes through the nasal cannula.
Moreover, known systems and methods for transnasal delivery often result in very low deposition efficiencies of aerosol deposition in the lung due to aerosol impaction in the nasal passages. For example, a study by Chua et al. showed overall deposition efficiencies of less than about three percent (as compared with deposition efficiencies of approximately 15 percent or higher for oral delivery of aerosolized medicaments). In particular, the study showed that only 0.3% of the emitted dose was deposited in the lungs in infants 0.3 to 1.4 month of age; only 2.9% of the emitted dose deposited in the lungs of pediatric subjects 6.3 to 11.5 years of age; and only 2.7% of the emitted dose deposited in the lungs of subjects 15 years of age and older. (See generally H Chua et al., Eur. Respir. J. 7, 2185-2191 (1994)). More recently, Vecellio et al. reported a 3.7% pulmonary deposition efficiency based on the dose from a nasal sonic jet nebulizer.
Thus, a need exists for improved compositions, systems and methods for delivering medicaments transnasally into the lungs.